A quarter of breast cancer patients whose disease had recurred or progressed during treatment with an aromatase inhibitor had partial responses or prolonged stable disease when treated with sorafenib (Nexavar) and anastrozole (Arimidex), Deepa Subramaniam, M.D., of Georgetown University, said at the 2008 Breast Cancer Symposium.

"Given what we know about the ineffectiveness of sorafenib alone in metastatic breast cancer, we believe the benefit that we're seeing may be attributable to the restoration of sensitivity to aromatase inhibitors," commented senior investigator Claudine Isaacs, M.D., also of Georgetown.

"To manage breast cancer long term, it's apparent that we may need to continually switch drugs to keep up with how a cancer evolves and evades each approach."

Over time, most cases of hormone receptor-positive metastatic breast cancer develop resistance to endocrine therapy. Proposed mechanisms of resistance include activation of the ras-raf-MAPK pathway, said Dr. Subramaniam.

Because sorafenib targets and inhibits multiple kinases in the pathway, a rationale existed for evaluating the agent as a means of overcoming resistance to aromatase inhibitors, he said.

Dr. Subramaniam reported findings from an ongoing study that had accrued 27 patients. Study participants were postmenopausal women with receptor-positive metastatic breast cancer that had become unresponsive to aromatase inhibitors.

The patients had received no more than two prior chemotherapy regimens for metastatic disease.

Of the 27 patients, two had partial responses that lasted more than six months and five had stable disease for more than 24 weeks. Ten patients had progressed, and six were not evaluable for response.

The patients who had partial responses and prolonged stable disease translated into an overall clinical benefit of 26.08%.

Preliminary analysis of factors associated with clinical benefit suggests that a decline in circulating endothelial cells during the first week of treatment predicts response to therapy, the researchers said.

Dr. Subramaniam said agents that target other pathways, such as insulin-like growth factor receptor, might offer other approaches to overcome resistance to endocrine therapy.

The strategy of adding a targeted agent to another type also has applicability to other cancers, she added, noting that studies have demonstrated unusually high response rates in patients with lung cancers that have become resistant to erlotinib (Tarceva).

Dr. Subramaniam reported no disclosures. Dr. Isaacs is a member of Pfizer's speaker bureau.

Reviewed by Zalman S. Agus, MD Emeritus Professor University of Pennsylvania School of Medicine

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